Dithioacyldihydropyrazole carboxylic acid derivatives

ABSTRACT

Compounds having the formula ##STR1## wherein: R 1  is hydrogen, alkyl, aryl or arylalkyl; 
     R 2  is hydrogen and R 3  is hydrogen, hydroxy, alkoxy or halogen, or together R 2  and R 3  can be ═Q or --X--(CH 2 ) t  --X-- wherein X is oxygen or sulfur and t is 2 or 3; 
     R 4  is hydrogen or alkyl; 
     R 5  is hydrogen, alkyl or trifluoromethyl; 
     R 6  is alkyl of 1 to 20 carbon atoms, aryl, arylalkyl or a 5- or 6-membered heterocyclic group having 1 to 2 nitrogen, sulfur or oxygen atoms in the ring; 
     R 7  is aryl; 
     m is 0, 1 or 2; and 
     n is 1 or 2 
     have useful hypotensive activity.

This is a division of application Ser. No. 61,729, filed July 30, 1979, now U.S. Pat. No. 4,288,368.

RELATED APPLICATIONS

U.S. patent application Ser. No. 018,548, filed Mar. 8, 1979, now U.S. Pat. No. 4,211,786, issued July 8, 1980, discloses mercaptoacyldihydropyrazole carboxylic acid derivatives having the formula ##STR2## wherein R_(a) is hydrogen, alkyl, aryl, arylalkyl, ##STR3## b is 0, 1 or 2; R_(c) is hydrogen or alkyl; R_(d) is aryl; and R_(e) is hydrogen, alkyl or arylalkyl.

U.S. patent application Ser. No. 972,314, filed Dec. 22, 1978, now abandoned, discloses mercaptoacyl proline derivatives having the formula ##STR4## wherein, R_(f) is hydrogen, acyl or ##STR5## R_(g), R_(i), R_(j) and R_(n) each is hydrogen or alkyl; X, and X₂ each is oxygen or sulfur; R_(k) and R_(m) each is alkyl or R_(k) and R_(m) join in a 2- or 3-carbon polymethylene chain to complete a 5- or 6-membered ring; and h is 0, 1 or 2.

U.S. patent application Ser. No. 52,691, filed July 2, 1979 discloses mercaptoacyl proline derivatives having the formula ##STR6## wherein R_(p) is hydrogen, acyl, or ##STR7## R_(q) and R_(s) each is hydrogen, alkyl or trifluoromethyl; r is 0, 1 or 2; X₃ is oxygen or sulfur; R_(t) is alkyl, alkenyl, alkynyl, aryl or aryl-lower alkylene; and R_(u) hydrogen or alkyl.

U.S. patent application Ser. No. 37,255, filed May 9, 1979, now U.S. Pat. No. 4,241,076, discloses halogen substituted mercaptoacylprolines having the formula ##STR8## wherein R_(v) is hydrogen, alkanoyl, phenylalkylenecarbonyl, or ##STR9## R_(w) is hydrogen, alkyl or trifluoromethyl; R_(x) is hydrogen, alkyl, halogen or trifluoromethyl; R_(y), R_(z) and R_(aa) each is hydrogen or halogen; R_(bb) is hydrogen or alkyl; and a_(l) is 0 or 1.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,105,776, issued Aug. 8, 1978, describes a group of thioalkanoyl derivatives of azetidinepyrrolidine-, and piperidinecarboxylic acid compounds having the formula ##STR10## wherein R_(cc) is hydrogen, alkyl, aryl, phenylalkyl, diphenylalkyl, triphenylalkyl, alkylthiomethyl, phenylalkylthiomethyl, alkanoylamidomethyl, ##STR11## R_(ii) --S--, or R_(jj) ; R_(dd) and R_(ee) each is hydrogen, phenyl, alkyl, or phenylalkyl; R_(ff) is hydrogen, hydroxy or alkyl; R_(gg) is hydroxy, --NH₂, or alkoxy; y₁ is 0, 1 or 2; y₂ is 1, 2, or 3; R_(hh) is alkyl, phenyl or phenylalkyl; R_(ii) is alkyl, aryl, hydroxyalkyl, or amino(carboxy)alkyl; R_(jj) is ##STR12## and y₃ is 0, 1 or 2.

The compounds set forth above, under the headings "Related Applications" and "Background of the Invention" are disclosed as being useful as inhibitors of the conversion of the decapeptide angiotensin I to angiotensin II. They are, therefore, useful in reducing or relieving angiotensin related hypertension.

BRIEF DESCRIPTION OF THE INVENTION

Compounds having the formulas ##STR13## and basic salts thereof, have hypotensive activity. In formulas I and II, and throughout the specification, the symbols are as defined below.

R₁ is hydrogen, alkyl, aryl or arylalkyl;

R₂ is hydrogen and R₃ is hydrogen, hydroxy, alkoxy or halogen, or together R₂ and R₃ can be ═O or --X--(CH₂)_(t) --X-- wherein X is oxygen or sulfur and t is 2 or 3;

R₄ is hydrogen or alkyl;

R₅ is hydrogen, alkyl or trifluoromethyl;

R₆ is alkyl of 1 to 20 carbon atoms, aryl, arylalkyl or a 5- or 6-membered heterocyclic group having 1 or 2 nitrogen, sulfur or oxygen atoms in the ring;

R₇ is aryl;

m is 0, 1 or 2; and

n is 1 or 2.

The term "aryl," as used throughout the specification, either by itself or as part of a larger group, refers to phenyl or phenyl substituted with 1, 2 or 3 halogen, alkyl, alkoxy, sulfamyl, hydroxy, ##STR14## nitro, amino, alkylamino, dialkylamino, trifluoromethyl, cyano or carboxyl groups. Phenyl is the preferred aryl group.

The terms "alkyl" and "alkoxy," as used throughout the specification (unless otherwise defined), either by themselves or as part of a larger group, refer to groups having 1 to 7 carbon atoms. Groups having 1, 2 or 3 carbon atoms are preferred.

The term "halogen," as used throughout the specification, either by itself or as part of a larger group, refers to fluorine, chlorine, bromine and iodine.

Exemplary of the heterocyclic "R₆ substituents" are thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholinyl and piperazinyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formulas I and II are useful as hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudo-globulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs. The compounds of this invention intervene in the angiotensinogen→(renin)→angiotensin I→(ACE)→angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one, or a combination of compounds, of formulas I and II angiotensin dependent hypertension in the species of mammal suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day, preferably about 1 to 15 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises (for a 70 kg. mammal) a total daily dosage of about 30 to 600 mg., preferably about 30 to 300 mg., of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorthiazide, hydrochlorthiazide, flumethiazide, hydroglumethiazide, bendroflumethiazide, methychlothiazide, trichlormethiazide, polythiazide, or benzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone, and salts of such compounds.

The compounds of formulas I and II can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The compounds of this invention can be obtained utilizing as a starting material the corresponding mercapto compound having the formula ##STR15## The compounds of formulas III and IV, and methods for their preparation are disclosed in U.S. Pat. Nos. 4,105,776, issued Aug. 8, 1978, and 4,154,935, issued May 15, 1979, and in U.S. patent applications Ser. Nos. 972,314, filed Dec. 22, 1978; 018,548, filed Mar. 8, 1979; 37,255, filed May, 9, 1979; 52,691, filed July 2, 1979. The disclosures of the above references are incorporated herein by reference.

Reaction of a compound of formula III or IV with a nitrile having the formula

    R.sub.6 --C.tbd.N                                          (V)

yields the corresponding imino ether having the formula ##STR16## The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane or chloroform, or ether. The reaction proceeds most readily in the presence of anhydrous hydrogen chloride.

Reaction of an imino ether of formula VI or VII with hydrogen sulfide in the presence of an organic base e.g., pyridine, yields the corresponding product of formula I or II. The reaction can be conveniently run by saturating a suspension (or solution) of a compound of formula VI or VII with hydrogen sulfide gas.

Alternatively, the products of this invention can be prepared by first reacting a nitrile of formula V with a mercapto carboxylic acid having the formula ##STR17## to yield a dithio ester having the formula ##STR18## The reaction can be run following the procedure described above for the reaction of a compound of formulas III or IV with a compound of formula V.

A compound of formula IX can be coupled with an amino acid ester having the formula ##STR19## wherein R₁ ' is alkyl, aryl or arylalkyl, using known procedures to obtain the products of formula I and II. For example, a dithio ester of formula IX can be activated prior to its reaction with an ester of formula X or XI by formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester or the like. Those products of this invention wherein R₁ is hydrogen can be prepared by saponification of a corresponding ester.

Another method for the preparation of the products of this invention comprises the alkylation of a dithioacid having the formula ##STR20## wherein R₈ is hydrogen or a cation such as ammonium or an alkali metal, with the appropriate halocarboxylic acid having the formula ##STR21## wherein R₉ is halogen or tosyl. The preparation of diothioacids of formula XII is described in Houben-Weyl, Methoden der Organischen Chemie, Vol. 9, Thieme Verlag, Stuttgart, 1955 and in Barton and Ellis, Comprehensive Organic Chemistry, Vol. 3, Pergamon Press, 1979.

Still another method for the preparation of the products of this invention comprises the thioacylation of a mercaptoamino acid of formula III or IV with a thioacid chloride having the formula ##STR22## wherein R₁₀ is chlorine or bromine.

The compounds of this invention form salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.

The compounds of formulas I and II each contains at least one asymmetric carbon and accordingly exist in stereoisomeric forms or in racemic mixtures thereof. The above described syntheses can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional fractional crystallization of the diastereomeric salt mixture formed, e.g., with an optically active amine. It is theorized that the activity of the racemic products is due mostly to the L-isomer with respect to the carbon of the amino acid, and this isomer is accordingly preferred.

The following examples are specific embodiments of this invention.

EXAMPLE 1 (S)-1-[2-Methyl-1-oxo-3-[(phenylthioxomethyl)thio]propyl]-L-proline

A solution of 4.4 g (0.02 mole) of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 5 g (˜0.05 mole) of benzonitrile in 50 ml of methylene chloride is cooled to 0° C., saturated with hydrogen chloride and stirred for about 16 hours at room temperature. The solvent is removed in vacuo and the residue is triturated with petroleum ether; the solvent is decanted.

To the residue is added 50 ml of pyridine and the mixture is stirred vigorously and cooled to 0° C. Hydrogen sulfide is bubbled through the mixture for 3 hours. The mixture is poured into ice water, acidified with concentrated hydrochloric acid and extracted exhaustively with ethyl acetate. The organic layers are combined, dried (MgSO₄) and evaporated in vacuo to give a residue which is crystallized from ethyl acetate to give 2.1 g of the title compound, melting point 157°-158° C.

Analysis calc'd for C₁₆ H₁₉ NO₃ S₂ : C,56.95; H,5.68; N,4.15. Found: C,57.10; H,5.78 N,4.34.

EXAMPLE 2 (S)-1-[3-[[(4-Fluorophenyl)thioxomethyl]thio]-2-methyl-1-oxopropyl]-L-proline

A solution of 4.4 g (0.02 mole) of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 5 g (˜0.04 mole) of p-fluorobenzonitrile in 50 ml of methylene chloride is cooled to 0° C., saturated with hydrogen chloride and stirred for about 16 hours at room temperature. The solvent is removed in vacuo and the residue is triturated with petroleum ether; the solvent is decanted.

To the residue is added 50 ml of pyridine and the mixture is stirred vigorously and cooled to 0° C. Hydrogen sulfide is bubbled through the mixture for three hours. The mixture is poured into ice water, acidified with concentrated hydrochloric acid and extracted exhaustively with ethyl acetate. The organic layers are combined, dried, (MgSO₄) and evaporated in vacuo to give a residue which is crystallized from ethyl acetate to give 2.2 g of the title compound, melting point 114°-115° C.

Anal. Calc'd for C₁₆ H₁₈ FNO₃ S₂ : C,54.06; H,5.10 N,3.94. Found: C,54.22; H,5.26 N,3.98.

EXAMPLE 3 (S)-1-[2-Methyl-1-oxo-3-[(2-thienylthioxomethyl)thio]propyl]-L-proline

A solution of 4.4 g (0.02 mole) of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 5 g (0.05 mole) of 2-thiophenecarbonitrile in 50 ml of methylene chloride is cooled to 0° C., saturated with hydrogen chloride and stirred for about 16 hours at room temperature. The solvent is removed in vacuo and the residue is triturated with petroleum ether; the solvent is decanted.

To the residue is added 50 ml of pyridine and the mixture is stirred vigorously and cooled to 0° C. Hydrogen sulfide is bubbled through the mixture for 3 hours. The mixture is poured into ice water, acidified with concentrated hydrochloric acid and extracted exhaustively with ethyl acetate. The organic layers are combined, dried (MgSO₄) and evaporated in vacuo to give a residue which crystallizes from ethyl acetate to give 3.5 g of the title compound, melting point 149°-150° C.

Anal. Calc'd for C₁₄ H₁₇ NO₃ S₃ : C,48.95; H,4.99; N,4.08. Found: C,49.15; H,5.13; N,4.21.

EXAMPLE 4 (S)-1-[2-Methyl-1-oxo-3-[(1-thioxoethyl)thio]propyl]-L-proline

To a solution of 2.2 g of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline, 5.1 ml of acetonitrile and 20 ml of methylene chloride is added 2 g of hydrogen chloride gas. The solution is allowed to stand for about 16 hours. The solvent is evaporated and the oily residue washed once with petroleum ether. The residue is treated with 50 ml of pyridine and hydrogen sulfide gas is introduced for three hours. The mixture is poured onto ice, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The dried extract is evaporated to yield an oily residue which, on trituration with cold ether, solidifies, yielding 1.1 g of product. Recrystallization from acetonitrile yields the title compound, melting point 123°-125° C.

Anal. Calc'd for C₁₁ H₁₇ NO₃ S₂ : C,47.97; H,6.22 N,5.09. Found: C,48.16; H,6.09; N,5.26.

EXAMPLE 5 (S)-1-[2-Methyl-1-oxo-3-[(1-thioxooctadecyl)thio]propyl]-L-proline

A solution of 2.2 g (0.01 mole) of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 5.2 g (0.02 mole) of stearonitrile in 70 ml of methylene chloride is cooled to 0° C., saturated with hydrogen chloride and stirred for about 16 hours at room temperature. The solvent is removed in vacuo and the residue is triturated with petroleum ether; the solvent is decanted.

To the residue is added 50 ml of pyridine and the mixture is stirred vigorously and cooled to 0° C. Hydrogen sulfide is bubbled through the mixture for 3 hours. The mixture is poured into ice water, acidified with concentrated hydrochloric acid and extracted exhaustively with ethyl acetate. The organic layers are combined, dried (MgSO₄) and evaporated in vacuo to give a residue which is crystallized from ether/petroleum ether to yield 1.7 g of the title compound, melting point 50°-51° C. 

What is claimed is:
 1. A compound having the formula ##STR23## or a non-toxic physiologically acceptable basic salt thereof, wherein R₁ is hydrogen, alkyl, aryl or arylalkyl;R₄ is hydrogen or alkyl; R₅ is hydrogen, alkyl or trifluoromethyl; R₆ is thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholinyl, or piperazinyl; R₇ is aryl; and m is 0, 1 or 2;wherein the term "aryl" refers to phenyl or phenyl substituted with 1, 2 or 3 halogen, alkyl, alkoxy, sulfamyl, hydroxy, ##STR24## nitro, amino, alkylamino, dialkylamino, trifluoromethyl, cyano or carboxyl groups and the terms "alkyl" and "alkoxy," unless otherwise defined, refer to groups having 1 to 7 carbon atoms.
 2. A compound in accordance with claim 1 wherein R₁ is hydrogen.
 3. A compound in accordance with claim 1 wherein R₇ is phenyl.
 4. A compound in accordance with claim 1 wherein R₄ and R₅ each is hydrogen and m is
 1. 